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EP3121171B1 - Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine - Google Patents

Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine Download PDF

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EP3121171B1
EP3121171B1 EP16167355.3A EP16167355A EP3121171B1 EP 3121171 B1 EP3121171 B1 EP 3121171B1 EP 16167355 A EP16167355 A EP 16167355A EP 3121171 B1 EP3121171 B1 EP 3121171B1
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Prior art keywords
phenyl
isopropoxy
piperidin
chloro
diamine
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German (de)
English (en)
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EP3121171A1 (fr
Inventor
Lili Feng
Baoqing Gong
Piotr H. Karpinski
Liladhar Murlidhar Waykole
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Novartis AG
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Novartis AG
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Priority to RS20181240A priority Critical patent/RS57771B1/sr
Priority to EP18186197.2A priority patent/EP3453708B8/fr
Priority to SI201131583T priority patent/SI3121171T1/sl
Priority to PL16167355T priority patent/PL3121171T3/pl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention is directed to crystalline forms of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine, methods of making the same, pharmaceutical compositions comprising the same and to the mentioned compound for use in methods of treatment.
  • Polymorphism denotes the existence of more than one crystalline form of a substance. This ability of a chemical substance to crystallize in more than one crystalline form can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug. In addition, the action of a drug can be affected by the polymorphism of the drug molecule. Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity. The occurrence of an unknown crystalline form during manufacture can have a significant impact.
  • the compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine, in the form of a free base, of formula is an anaplastic lymphoma kinase (ALK) inhibitor, a member of the insulin receptor super family of receptor tyrosine kinases.
  • ALK anaplastic lymphoma kinase
  • WO 2008/073687 A1 provides no information about crystalline forms of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine or its corresponding salts.
  • Crystalline forms of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine have been discovered, which are useful in treating diseases which respond to inhibition of anaplastic lymphoma kinase activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70) insulin-like growth factor (IGF-1R or a combination thereof.
  • FAK focal adhesion kinase
  • ZAP-70 zeta-chain-associated protein kinase 70
  • IGF-1R insulin-like growth factor
  • the crystalline forms exhibit new physical properties that may be exploited in order to obtain new pharmacological properties, and that may be utilized in the drug product development of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.
  • the present invention provides substantially pure crystalline forms of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a therapeutically effective amount of a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine; and (b) at least one pharmaceutically acceptable carrier.
  • the present description also provides a method for the preparation of a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine which comprises the step of: reacting 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent with at least two equivalents of aqueous sodium hydroxide.
  • the present description also provides a method for the preparation of a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine which comprises the step of: heating a mixture of two crystalline forms of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine in a solvent.
  • the present disclosure also provides 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine for use in a method for the treatment of disorders mediated by anaplastic lymphoma kinase, comprising administering to a patient in need of such treatment an effective amount of a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.
  • the present invention also provides the use of a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine for the preparation of a medicament for the treatment of disorders mediated by anaplastic lymphoma kinase.
  • the present invention also provides the use of the mentioned compound for the preparation of a medicament for the treatment of disorders selected from benign or malignant tumor; a cancer selected from anaplastic large cell lymphoma; non-Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung; non-small cell lung cancer; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute mye
  • XRPD X-ray powder diffraction
  • the term "substantially pure” means that more than 80% of one crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine or salt thereof is present or isolated, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of one of the crystalline forms described herein is present.
  • crystalline form A a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine is isolated, referred to as crystalline form A.
  • Form A of the free base is relatively non-hygroscopic at 84% relative humidity (RH) and exhibits minor increase in moisture uptake at 93% RH. It has good solubility at pH 1, fair solubility in water and good solubility in organic solvents (11 mg/mL in pH 1, 0.21 mg/mL in water and 40 mg/mL in methanol, respectively). It is converted to a hydrochloride salt (non-stoichiometric) in pH 1 (0.1N HCl) solution over 72 hour. The pH of 1% suspension in water is 6.86.
  • the XRPD of crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine exhibits diffraction peaks having maxima at diffraction angles 7.2°, 8.1°, 10.8°, 12.0°, 12.4°, 13.4°, 14.4°, 14.8°, 15.7°, 16.9°, 17.7°, 18.5°, 19.0°, 19.5°, 20.0°, 20.3°, 21.1°, 21.6°, 22.4°, 22.6°, 23.0°, 24.1°, 24.5°, 25.5°, 26.0°, 26.2°, 27.0°, 27.3°, 28.3°, 29.0°, 29.1°, 30.6°, 31.3°, 32.8°, 33.5°, 34.2° and 36.4° (2 ⁇ degrees), as summarized by the X
  • Crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine exhibits the following thermal parameters: melting point, Tm (onset) 174° C as determined by differential scanning calorimetry at a scanning rate of 10° C/min. ( Figure 2 ), decomposition point, T > 250° C, and a weight loss on drying of 0.1% at 200° C, as determined by thermogravimmetric analysis and summarized in Figure 3 .
  • crystalline form B a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine is isolated, referred to as crystalline form B.
  • Crystalline form B of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine exhibits the following thermal parameters: melting point, Tm (onset) 162° C as determined by differential scanning calorimetry at a scanning rate of 10° C/min. ( Figure 5 ), decomposition point, T > 250° C, and a weight loss on drying of 0.05% at 200° C, as determined by thermogravimmetric analysis and summarized in Figure 6 .
  • the present invention provides a method for the preparation substantially pure crystalline forms of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.
  • the crystalline forms are prepared from a solvent or mixed solvents comprising a good solvent, in which the compound is readily soluble, and a poor solvent, in which it is more sparingly soluble, may also be employed provided that crystallization from the mixture is possible using the selected solvent mixture.
  • Examples of good solvents include methanol, ethanol and isopropanol, formic acid, acetic acid, ethyl acetate, tetrahydrofuran and acetone.
  • An example of a poor solvent is e.g., water.
  • crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine is prepared by reacting 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in aqueous acetone with at least two equivalents of aqueous sodium hydroxide.
  • the ratio of acetone:water usefully employed in accordance with the invention ranges from 1:1 to 5:1 and 1:1 to 1:5 (volume:volume, v/v), including 1:1 and 3:1.
  • the reaction temperature ranges from 20° to 70° C, including 55° C.
  • the crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine contains less than 1% by weight total impurities. In another embodiment, the polymorph form A contains less than 0.5% by weight total impurities. In yet another embodiment, the polymorph form A contains less than 0.1 % by weight total impurities.
  • crystalline form B of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine is prepared by reacting 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine with aqueous hydrochloric acid and subsequently adding sodium hydroxide.
  • the reaction temperature ranges from 20° C to 70° C
  • crystalline form B of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine is converted to crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine by adding a small amount of crystalline form A (1% by weight or less, referred to as seeding) to a suspension or solution of form B of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine in aqueous acetone.
  • seeding
  • seed can be used as a noun to describe one or more crystals of a crystalline compound of formula I.
  • the term “seed” can also be used as a verb to describe the act of introducing said one or more crystals of a crystalline compound of formula I into an environment (including, but not limited to e.g., a solution, a mixture, a suspension, or a dispersion) thereby resulting in the formation of more crystals of the crystalline compound of formula I.
  • crystalline form B of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine is converted to crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine by heating a suspension or solution containing crystalline form B of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine in aqueous acetone.
  • Mixed solvents usefully employed include, for example, acetone/water and ethanol/water.
  • the ratio of acetone:water usefully employed ranges from 1:1 to 5:1 (volume:volume, v/v), including 1:1 and 3:1.
  • the reaction temperature ranges from 30° to 70° C, including 50° C.
  • a pharmaceutical composition comprising: (a) a therapeutically effective amount of a substantially pure crystalline form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine; and (b) at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises: (a) a therapeutically effective amount of a substantially pure crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine; and (b) at least one pharmaceutically acceptable carrier.
  • the at least one pharmaceutically acceptable carrier is in the form of a diluent, vehicle or excipient and can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
  • suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
  • the pharmaceutical compositions of this invention may take any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.
  • the medicament comprises: (a) a therapeutically effective amount of a substantially pure crystalline form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.
  • the medicament is useful in treating diseases which respond to inhibition of anaplastic lymphoma kinase activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70) insulin-like growth factor (IGF-1R and combinations thereof.
  • FAK focal adhesion kinase
  • ZAP-70 zeta-chain-associated protein kinase 70
  • IGF-1R insulin-like growth factor
  • the diseases are selected from benign or malignant tumor; a cancer selected from anaplastic large cell lymphoma; non-Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; my
  • a “therapeutically effective amount” is intended to mean the amount of the inventive crystalline form that, when administered to a subject in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of protein kinase activity.
  • the amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the disease condition and the severity thereof, the identity of the subject in need thereof, etc., which amount may be routinely determined by artisans of ordinary skill in the art.
  • Preferably, more than 80%, more preferably at least 85%, still more preferably at least 90%, and most preferably at least 95%, of the crystalline form administered is of one of the inventive forms.
  • illustrative modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
  • Administration of the crystalline form may be accomplished by administration of a pharmaceutical composition of this invention or via any other effective means.
  • the reaction mixture was maintained at 55 ⁇ 3 °C for an additional 2 hours to yield an off-white slurry.
  • An additional 10.82 g (about 58% by weight) of aqueous NaOH solution was added to the hot solution over a period of 1.5 hours to yield a thick off-white slurry.
  • the slurry was cooled to 20 ⁇ 3 °C over a period of about 45 minutes and 47.0 g of deionized (DI) water was added over about 30 minutes and the off-white slurry was stirred at 20 ⁇ 3 °C for 1 hour.
  • the slurry was filtered and rinsed with 2 ⁇ 25.0 g of DI water.
  • Form A of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine by seeding a suspension of Form B of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine with Form A
  • a small amount of crystalline form A of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine (0.1-1.0 % by weight) was added to a suspension of crystalline form B of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine in aqueous acetone with stirring at room temperature.
  • the crystalline form was analyzed by its corresponding turbidity profile or by XRPD.
  • the amount of substantially pure form A obtained is influenced by the solvent, ratio of acetone to water by volume and the amount of "seed" A used, as summarized in Table 1.
  • Table 1 Seeding of Crystalline Form B with Form A.
  • Solvent System Acetone water (v/v) Form A "Seed” (weight %) XRPD after 24 hours 1:9 1.0 Form B + Form A 1:9 0.1 Form B 3:7 1.0 Form A 3:7 0.1 Form B + Form A 1:1 1.0 Form A (at 2 hours) 1:1 0.1 Form A (at 4 hours)
  • Form B of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine Conversion of Form B of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine to Form A of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine by heating in an aqueous solvent

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Claims (4)

  1. Forme cristalline de 5-chloro-N2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-N4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine.
  2. Composition pharmaceutique comprenant une forme cristalline selon la revendication 1, et un véhicule pharmaceutiquement acceptable.
  3. Utilisation d'une forme cristalline de 5-chloro-N2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-N4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine pour la préparation d'un médicament pour le traitement de troubles médiés par la lymphome kinase anaplasique.
  4. Utilisation selon la revendication 3, dans laquelle le trouble est un cancer choisi parmi un lymphome anaplasique à grandes cellules ; un lymphome non hodgkinien ; une tumeur myofibroblastique inflammatoire ; un neuroblastome ; un sarcome ; un cancer du poumon ; un cancer du poumon non à petites cellules ; un cancer des bronches ; de la prostate ; du sein (comprenant les cancers du sein sporadiques et les personnes atteintes de la maladie de Cowden) ; du pancréas ; un cancer gastro-intestinal; du côlon ; du rectum ; un carcinome du côlon ; un adénome colorectal ; un cancer de la thyroïde ; du foie; des voies biliaires intrahépatiques ; hépatocellulaire ; des glandes surrénales ; de l'estomac ; gastrique ; un gliome ; un glioblastome ; un cancer de l'endomètre ; un mélanome ; un cancer du rein; du bassinet du rein; de la vessie ; du corpus utérin ; du col de l'utérus ; du vagin ; de l'ovaire ; un myélome multiple ; un cancer de l'oesophage; une leucémie ; une leucémie myéloïde aiguë ; une leucémie myéloïde chronique ; une leucémie lymphocytaire ; une leucémie myéloïde ; un cancer du cerveau ; un carcinome du cerveau ; un cancer de la cavité buccale et du pharynx ; du larynx ; de l'intestin grêle ; et un mélanome.
EP16167355.3A 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine Active EP3121171B1 (fr)

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RS20181240A RS57771B1 (sr) 2010-12-17 2011-12-15 Kristalni oblici 5-hloro-n2-(2-izopropoksi-5-metil-4-piperidin-4-il-fenil)-n4-[2-(propan-2-sulfonil)-fenil]-pirimidin-2,4-diamina
EP18186197.2A EP3453708B8 (fr) 2010-12-17 2011-12-15 Procédé pour la préparation de 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)phenyl]-pyrimidine-2,4-diamine di-hydrochloride
SI201131583T SI3121171T1 (sl) 2010-12-17 2011-12-15 Kristalinične oblike 5-kloro-N2-(2-izopropoksi-5-metil-4-piperidin-4-il-fenil)-N4-(2- (propan-2-sulfonil)-fenil)-pirimidin-2,4-diamina
PL16167355T PL3121171T3 (pl) 2010-12-17 2011-12-15 Krystaliczne postaci 5-chloro-N2-(2-izopropoksy-5-metylo-4-piperydyn-4-ylofenylo)-N4-[2-(propano-2-sulfonylo)-fenylo]-pirymidyno-2,4-diaminy
HRP20181737TT HRP20181737T1 (hr) 2010-12-17 2018-10-22 Kristalni oblici od 5-kloro-n2-(2-izopropoksi-5-metil-4-piperidin-4-il-fenil)-n4-[2-(propan-2-sulfonil)-fenil]-pirimidin-2,4-diamina

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US201061424194P 2010-12-17 2010-12-17
EP11806079.7A EP2651918B1 (fr) 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
PCT/US2011/065030 WO2012082972A1 (fr) 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine

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EP11806079.7A Division-Into EP2651918B1 (fr) 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine

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EP11806079.7A Revoked EP2651918B1 (fr) 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
EP16167355.3A Active EP3121171B1 (fr) 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine

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EP11806079.7A Revoked EP2651918B1 (fr) 2010-12-17 2011-12-15 Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine

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CN104262324A (zh) 2015-01-07
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RU2016136823A3 (fr) 2020-02-06
MY177742A (en) 2020-09-23
KR102325775B1 (ko) 2021-11-12
RU2013132947A (ru) 2015-01-27
CY1119474T1 (el) 2018-04-04
CO6801792A2 (es) 2013-11-29
GT201300153A (es) 2014-06-09
US20130274279A1 (en) 2013-10-17
CN106831716A (zh) 2017-06-13
SG190856A1 (en) 2013-07-31
RU2599785C2 (ru) 2016-10-20
KR20180032680A (ko) 2018-03-30
RU2599785C3 (ru) 2019-04-24
PH12013501254A1 (en) 2016-07-29
SI3121171T1 (sl) 2018-11-30
TW201307299A (zh) 2013-02-16
ECSP13012770A (es) 2013-10-31
CN107056751A (zh) 2017-08-18
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CL2013001723A1 (es) 2013-12-27
US20160175305A1 (en) 2016-06-23
KR20190022903A (ko) 2019-03-06
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ZA201303599B (en) 2014-02-26
IL226474A (en) 2016-03-31
EP3453708A1 (fr) 2019-03-13
DK2651918T3 (en) 2017-10-23
CY1121017T1 (el) 2019-12-11
CA2821102C (fr) 2019-06-11
PT2651918T (pt) 2017-10-17
PE20140698A1 (es) 2014-06-11
TWI576344B (zh) 2017-04-01
DK3121171T3 (en) 2018-12-10
PL2651918T3 (pl) 2017-12-29
AU2011343775B2 (en) 2015-12-03
AR084309A1 (es) 2013-05-08
EP2651918B1 (fr) 2017-07-12
AU2011343775A1 (en) 2013-07-18
CN106008462A (zh) 2016-10-12
ES2696526T3 (es) 2019-01-16
JP5916752B2 (ja) 2016-05-11
ES2643016T3 (es) 2017-11-21
US9309229B2 (en) 2016-04-12
EP2651918A1 (fr) 2013-10-23
TW201629021A (zh) 2016-08-16
EP3121171A1 (fr) 2017-01-25
HRP20171477T1 (hr) 2017-11-17
MY164810A (en) 2018-01-30
CN103282359A (zh) 2013-09-04
LT2651918T (lt) 2017-10-10
SI2651918T1 (sl) 2017-10-30
RU2746159C2 (ru) 2021-04-08
MX2013006952A (es) 2013-07-15
JP2013545812A (ja) 2013-12-26
CA2821102A1 (fr) 2012-06-21
TWI576343B (zh) 2017-04-01
EP3453708B1 (fr) 2021-10-27
WO2012082972A1 (fr) 2012-06-21
KR20130130022A (ko) 2013-11-29
TN2013000216A1 (en) 2014-11-10
PL3121171T3 (pl) 2019-01-31
KR20200039021A (ko) 2020-04-14
SG10201510082XA (en) 2016-01-28
MA34771B1 (fr) 2013-12-03
CN112125884A (zh) 2020-12-25
HUE041845T2 (hu) 2019-05-28
HRP20181737T1 (hr) 2018-12-28
CN114989139A (zh) 2022-09-02
RU2016136823A (ru) 2018-12-11
RS57771B1 (sr) 2018-12-31
BR112013015000A2 (pt) 2016-08-09
PT3121171T (pt) 2018-11-27
LT3121171T (lt) 2018-11-12
IL226474A0 (en) 2013-07-31

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